ClinVar Genomic variation as it relates to human health
NM_001267550.2(TTN):c.39974-11T>G
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001267550.2(TTN):c.39974-11T>G
Variation ID: 987382 Accession: VCV000987382.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q31.2 2: 178649342 (GRCh38) [ NCBI UCSC ] 2: 179514069 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 28, 2020 Apr 15, 2024 Oct 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001267550.2:c.39974-11T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001256850.1:c.35374+475T>G intron variant NM_003319.4:c.13283-7025T>G intron variant NM_133378.4:c.32593+475T>G intron variant NM_133432.3:c.13658-7025T>G intron variant NM_133437.4:c.13859-7025T>G intron variant NC_000002.12:g.178649342A>C NC_000002.11:g.179514069A>C NG_011618.3:g.186461T>G LRG_391:g.186461T>G - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:178649341:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TTN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
11689 | 31012 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2022 | RCV001268728.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 15, 2023 | RCV001880170.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 26, 2021 | RCV002491873.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2023 | RCV003225966.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 15, 2023 | RCV003393938.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447870.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Arthrogryposis multiplex congenita (present)
Sex: female
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Likely pathogenic
(Oct 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tibial muscular dystrophy
Myopathy, myofibrillar, 9, with early respiratory failure Dilated cardiomyopathy 1G Autosomal recessive limb-girdle muscular dystrophy type 2J Early-onset myopathy with fatal cardiomyopathy Hypertrophic cardiomyopathy 9
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002798870.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001767621.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
Published mRNA functional studies demonstrate this variant results in two abnormally spliced transcripts (Bryen et al., 2019); In silico analysis supports a deleterious effect on … (more)
Published mRNA functional studies demonstrate this variant results in two abnormally spliced transcripts (Bryen et al., 2019); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31660661, 33977140) (less)
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Pathogenic
(May 02, 2023)
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criteria provided, single submitter
Method: curation
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TTN-related myopathy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003922359.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
The heterozygous c.39974-11T>G variant in TTN was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 577790), … (more)
The heterozygous c.39974-11T>G variant in TTN was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 577790), in one individual with congenital myopathy. Trio exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 577790). The c.39974-11T>G variant in TTN has been previously reported in eight unrelated individuals with titin-related myopathy (PMID: 31660661) but has been identified in 0.01% (4/41260) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758597536). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID:987382) and has been interpreted as pathogenic by Invitae, GeneDx, Institute of Medical Genetics and Applied Genomics, University Hospital Tvºbingen, and the CeGaT Center for Human Genetics Tuebingen. The eight unrelated affected individuals previously reported were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans (PMID: 31660661), which increases the likelihood that the c.39974-11T>G variant is pathogenic. RT-PCR and RNAseq analysis performed on skeletal muscle tissue from affected individuals shows altered splicing resulting in either use of a cryptic 3‚Ä= splice site that abnormally includes 10 nucleotides of intron 213, leading to a frameshift and premature termination or in-frame exon skipping of exon 214 leading to an in-frame deletion of 28 amino acids in one of the proline-glutamine-valine-lysine (PEVK) regions of the gene (PMID: 31660661). This variant is located in the 3‚Äô splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive titin-related myopathy. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting (Richards 2015). (less)
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Pathogenic
(Feb 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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TTN-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004118993.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TTN c.39974-11T>G variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous state with a second pathogenic TTN … (more)
The TTN c.39974-11T>G variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous state with a second pathogenic TTN variant in eleven individuals from ten families with autosomal recessive arthrogryposis multiplex congenita and myopathy (Table S1, Bryen SJ et al. 2020. PubMed ID: 31660661; Suppl. Table 2, Ravenscroft G et al. 2020. PubMed ID: 33060286). Functional studies show this variant causes abnormal splicing, resulting in a frameshift, or an in-frame deletion of 28 amino-acids caused by a skip of exon 214 (Bryen SJ et al. 2020. PubMed ID: 31660661). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179514069-A-C). Taken together, in the context of autosomal recessive TTN-related disorders, this variant is interpreted as pathogenic. However, RNAseq studies from heart tissue indicate this exon is not commonly included in TTN mRNA transcripts (PSI < 15%, Roberts AM et al. 2015. PubMed ID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). Of note, variants found in exons not spliced into titin isoforms expressed in the heart (non-cardiac exons with ‘Percent Spliced In’ (PSI) < 15%) are unlikely to be associated with dilated cardiomyopathy (DCM) (Schafer S et al. 2017. PubMed ID: 27869827). Therefore, in the context of autosomal dominant TTN-related disorders, this variant is interpreted as a variant of uncertain significance. (less)
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Pathogenic
(Oct 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1G
Autosomal recessive limb-girdle muscular dystrophy type 2J
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002208293.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 212 of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein. … (more)
This sequence change falls in intron 212 of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein. This variant is present in population databases (rs758597536, gnomAD 0.02%). This variant has been observed in individuals with autosomal recessive arthrogryposis multiplex congenita and myopathy (PMID: 31660661). ClinVar contains an entry for this variant (Variation ID: 987382). Studies have shown that this variant is associated with altered splicing, resulting in a premature frameshift or an in-frame loss of exon 213 (also known as exon 214) (PMID: 31660661). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001962330.14
First in ClinVar: Oct 08, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy. | Bryen SJ | Human mutation | 2020 | PMID: 31660661 |
Prevalence of Titin Truncating Variants in General Population. | Akinrinade O | PloS one | 2015 | PMID: 26701604 |
Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. | Roberts AM | Science translational medicine | 2015 | PMID: 25589632 |
Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. | Ceyhan-Birsoy O | Neurology | 2013 | PMID: 23975875 |
Truncations of titin causing dilated cardiomyopathy. | Herman DS | The New England journal of medicine | 2012 | PMID: 22335739 |
Text-mined citations for rs758597536 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.